Positron emission tomography (PET) is routinely used in the clinic for cancer detection, with the majority of all scans performed with the glucose analogue [18F]2-fluoro-2-deoxyglucose, [18F]FDG. A number of clinical studies, however, have shown poor sensitivity for the detection of certain cancers, for example, prostate cancer, by [18F]FDG-PET. Prostate cancer is the most prevalent of cancers in the male population, accounting for 40,841 incidents in the UK in 2009.1 In the USA prostate cancer is the second largest cause of cancer mortality amongst men. The poor sensitivity for prostate cancer detection by [18F]FDG-PET is thought to be a result of low basal glucose metabolism of some prostate tumours2 and the high renal clearance of [18F]FDG, which can often mask tumour uptake.3 As a result, other PET tracers have been developed for cancer imaging including as [11C] choline, [18F]choline and [11C]acetate.
[11C]Acetate was initially developed as a radiotracer to evaluate oxidative metabolism in the myocardium. Following entry into the cell, either by passive diffusion or membrane transport via the monocarboxylate transporters,4 [11C]acetate is converted to [11C]acetyl-CoA by acetyl CoA synthetase before its rapid metabolism via the citric acid cycle to [11C]CO2.5 As well as being a substrate for the citric acid cycle, acetyl-CoA also enters into the fatty acid synthesis pathway, with tumour-associated [11C]acetate accumulation shown to result from cell membrane incorporation following flux through the fatty acid synthesis pathway.
Experiments carried out by Yoshimoto and co-workers showed that [1-14C]acetate was incorporated into the lipid soluble fraction, mostly as phosphatidylcholine and neutral lipids. The accumulation of [1-14C] acetate was positively correlated with the growth of the tumour cells. Fatty acid synthase (FAS) has been shown to be overexpressed in cancer, accounting for the uptake of acetate into the fatty acid synthesis pathway and incorporation into the cell membrane.6,7 [11C]Acetate has shown great promise in imaging prostate cancer, but the short half-life of carbon-11 (20.4 min) requires an on-site cyclotron, limiting its wide-spread use. [18F]Fluoroacetate ([18F]FAC, 1) has been investigated as an alternative to [11C]acetate for imaging of prostate cancer. The radiotracer was introduced by Welch and co-workers.8 The advantage of using fluorine-18 is its longer half-life of 109.5 min compared to the carbon-11 half-life of 20.4 min.
The authors in reference 8 investigated the biodistribution of [11C]acetate and [18F]FAC (1) in Sprague-Dawley rats. They found fairly rapid clearance of [11C]acetate from most of organs except the pancreas at 1 h, whereas [18F]FAC clearance was slower from most organs. This is thought to be due the oxidative metabolism of [11C]acetate, releasing [11C]CO2. The main drawback of [18F] FAC is its substantial bone uptake, characteristic of radiotracer defluorination.9 A comparison with [11C]acetate did describe a sizeable amount of the injected dose of [18F]FAC was taken up by bones in pigs and less pronounced in monkeys. This unwanted and massive defluorination in pigs results in unspecific intense skeletal activity and imaging during PET, showing this tracer's limitations for use in higher animals. [18F]Fluoroacetate is not a functional analogue of [11C]acetate in normal physiology.9 There are a number of putative routes for defluorination (Scheme 1). Tecle and Casida, for example, found that incubation of [13C]fluoroacetate with rat and mouse liver cytosol leads to formation of S-([13C]carboxymethyl) glutathione (2) and fluoride ion indicating that the fluoride ion is displaced by the glutathione (GSH) via a nucleophilic attack. Once [18F]FAC enters the citric acid cycle, it is converted into 2-fluorocitrate 3. The same authors,10 together with other groups,11,12 showed that (−)-erythro-2-fluorocitrate is both a substrate and an inhibitor for aconitase, the latter is responsible for defluorination. The mechanism of defluorination requires the conversion of 2-fluorocitrate 3 into fluoro-cis-aconitate, which undergoes addition of hydroxide and subsequent loss of fluoride to form 4-hydroxy-trans-aconitate 4. Compound 4 binds very tightly to the enzyme and it is responsible for the toxicity of fluoroacetate at pharmacological levels.

Given the inadequate performance of [18F]FAC as a tracer that can be used to image biology of acetate metabolism preclinically in prostate cancer and beyond, there is an unmet need to provide a stable imaging agent which does not undergo de-labelling to lose its radionuclide label.
Dynamic nuclear polarization (DNP) of 13C-labeled molecules can increase their sensitivity of detection in a solution-state nuclear magnetic resonance experiment by >10,000 times.13 This dramatic increase in sensitivity means that, after intravenous injection, the spatial distribution of the labelled molecule and its subsequent metabolism can be imaged in vivo using 13C magnetic resonance spectroscopic imaging (MRSI) techniques. Tracking metabolic reactions in vivo by DNP has been exemplified with hyperpolarised [1-13C]pyruvate, whose metabolic products, [1-13C]lactate, [1-13C] alanine, and [13C]bicarbonate, have been shown to correlate with disease progression and response to therapy.
In tumours, the metabolic fate of [1-13C]pyruvate is label exchange to [1-13C]lactate, catalysed by lactate dehydrogenase, the final enzyme in the glycolytic pathway. Since the pyruvate blood-brain barrier (BBB) is rate limited,14 hyperpolarised [1-13C]pyruvate may have limited utility for determining disease-state under conditions where an intact BBB is present, for example, infiltrating gliomas, Alzheimer's disease, nonenhancing multiple sclerosis, and acute stroke. Unsubstituted [1-13C]propionate has previously been polarised to high levels by DNP, and its metabolic products imaged in vivo during ischemia.15 
There exists a need to provide imaging agents for DNP that can measure disease-state in the brain. Moreover, a measure of metabolic flux in pathways other than glycolysis may provide alternate and complementary prognostic information for diseases in other tissues of the body.